Project Summary: In the US, 14-21% of pregnant women are exposed to opioids during pregnancy. This re- flects a doubling of prescribed opioid use and opioid use disorder (OUD) in pregnancy in the past dec- ade. Opioid relapse during pregnancy and after delivery is high due to post-partum depression and other psy- chosocial factors. In parallel, neonatal abstinence syndrome (NAS) rates have increased more than 3 to 20 fold since 2000. Every 25 minutes, a baby is born dependent to opioids in the US. Children exposed to opioids pre- natally and in the neonatal period are at risk of opioid misuse later in life, and may develop cognitive, behavior- al and neurodevelopmental problems. All these preventable public health crises confer a significant societal and economic burden, with loss of productive life. Despite the high prevalence of exposure to opioids, little is known about the factors predisposing to poor maternal outcomes, and neurodevelopmental outcomes in chil- dren with maternal OUD. Further, the effect of in-utero opioid exposure on placental function, fetal maturation and neonatal brain activity are unknown. Tackling maternal opioid misuse and NAS requires a comprehensive understanding of multiple maternal-infant factors. There is a critical need for early and targeted identification of pregnant women with OUD at risk for relapse and poor long term maternal and childhood outcomes. Our long- term goals are to reduce future maternal OUD and relapse on opioid maintenance therapy, decrease severity of NAS, personalize NAS treatment, and improve neurodevelopment in children with in-utero opioid exposure. The objective of this proposal is to determine multi-factorial genetic, psychosocial predictors of opioid related maternal and infant outcomes using rigorous prospective longitudinal design, innovative combinatorial phar- macogenetic approach, fetal MRI and neonatal brain resting state functional MRI analysis. Our earlier work showed that maternal/neonatal genetic variations and opioid-pharmacogenetics were associated with NAS se- verity and adverse effects of opioids. Our preliminary data show that children treated for NAS had significantly worse cognitive function at two years of life. Based on our previous results, we hypothesize that a combination of maternal and infant genetic profile, maternal psychosocial factors, maternal opioid treatment response, fetal and neonatal neurodevelopment and NAS treatment will affect maternal and childhood outcomes with prenatal opioid exposure.The specific aims are to: 1) Identify high-risk genetic profiles and psychosocial factors in preg- nant women with opioid use disorder, and predisposing to poor maternal opioid maintenance treatment out- comes; 2) Determine maternal-infant genetic profiles and maternal opioid treatment factors predicting adverse fetal development, severity of NAS, and neonatal brain function; and 3) Develop predictive models for maternal opioid relapse, and poor long-term neuro-developmental outcomes in children with in-utero opioid exposure. Critical new knowledge from this research will enable safe, effective treatment of maternal-infant opioid expo- sure and neurodevelopmental outcomes by enabling proactive risk predictions and personalized interventions.